Retroviruses such as Gibbon Ape Leukemia Virus (GALV) are one of the mainstays of current gene therapy because they are FDA-approved as safe, and they provide stable expression of the genetic material they inject into the genome of target cells. GALV-based gene delivery vehicles have been successfully used in a number of human clinical trials of efficacy in correcting the genetic defect in X-SCID (X chromosome linked severe combined immunodeficiency disease) and in treating melanoma and other metastatic cancers. Our work focuses on identification of the rate-limiting steps in virus binding, fusion, stable integration and expression of GALV-based retroviral vectors as well as other gammaretroviral vectors. Our interest in host factors required for viral entry led to the identification of the GALV receptor as PiT1, a ubiquitous plasma membrane phosphate transporter. We went on to determine the receptors structure and discovered that PiT1 is the receptor not only for GALV but also for the recently discovered endogenizing leukemogenic koala retrovirus KoRV. An endogenous virus like KoRV differs from an exogenous infectious retrovirus like GALV in that it has integrated into the host germline and is inherited from host to offspring. Endogenous viruses undergo a process of becoming a "domesticated" genetic element in the host genome, thereby losing many of their pathogenic properties. Comparing the evolutionary relatedness of GALV and KoRV has led to the development of high-titer GALV gene delivery vectors that have lost many of the deleterious properties of wild-type GALV. This strategy will enable us to develop novel retroviruses that have the ideal compositions needed for construction of efficient, safe gene delivery vehicles for future gene therapy studies. Our work with gammaretroviruses like GALV has extended the range of target cells amenable to retroviral gene delivery to include neuronal progenitor cells and post-mitotic neurons. It has been previously proposed that gene delivery by retroviral vectors such as GALV occurs only in actively dividing cells. As a result, it was thought that cells such as neurons are resistant to infection by these vectors. However, in preliminary studies, we have found that our viruses do infect neurons, both in vitro and in vivo. Our expertise in understanding and controlling the determinants of retroviral entry allows us to design retroviral vectors that can be used to efficiently introduce genes into neurons. Our knowledge of vector development for gene therapy will be used to initiate translational studies aimed at introduction of foreign genes into neurons for the purpose of genetic treatment of diseases of the central nervous system.